Are we curing one evil with another? A translational approach targeting the role of neoatherosclerosis in late stent failure.

Neoatherosclerosis is defined as foamy macrophage infiltration into the peri-strut or neointimal area after stent implantation, potentially leading to late stent failure through progressive atherosclerotic changes including calcification, fibroatheroma, thin-cap fibroatheroma, and rupture with stent thrombosis (ST) in advanced stages. Human autopsy as well as intravascular imaging studies have led to the understanding of neoatherosclerosis formation as a similar but significantly accelerated pathophysiology as compared to native atherosclerosis. This acceleration is mainly based on disrupted endothelial integrity with insufficient barrier function and augmented transmigration of lipids following vascular injury after coronary intervention and especially after implantation of drug-eluting stents. In this review, we summarize translational insights into disease pathophysiology and discuss therapeutic approaches to tackle this novel disease entity. We introduce a novel animal model of neoatherosclerosis alongside accompanying in vitro experiments, which show impaired endothelial integrity causing increased permeability for low-density lipoprotein cholesterol resulting in foam cell transformation of human monocytes. In addition, we discuss novel intravascular imaging surrogates to improve reliable diagnosis of early stage neoatherosclerosis. Finally, a therapeutic approach to prevent in-stent neoatherosclerosis with magnesium-based bioresorbable scaffolds and systemic statin treatment demonstrated the potential to improve arterial healing and re-endothelialization, leading to significantly mitigated neoatherosclerosis formation in an animal model of neoatherosclerosis.

La neoateroesclerosis se define como infiltración de macrófagos espumosos en la zona periprotésica o de la neoíntima tras una implantación de stent, lo cual posiblemente derive en un fracaso tardío del stent mediante cambios ateroescleróticos progresivos, incluidos la calcificación, fibroateromas, fibroateromas de cápsula fina (FACF) y trombosis del stent (TS). Gracias a los estudios de autopsia humana y de imagen intravascular se ha podido comprender la formación de la neoateroesclerosis de una manera fisiopatológica similar a la ateroesclerosis nativa pero significativamente acelerada. Esta aceleración se basa principalmente en la alteración de la integridad endotelial con una función de barrera insuficiente y una mayor transmigración de lípidos a consecuencia de una lesión vascular tras una intervención coronaria y, especialmente, tras la implantación de stents farmacoactivos. En este artículo ofrecemos un resumen de las perspectivas translacionales sobre la fisiopatología de la enfermedad y analizamos los enfoques terapéuticos para abordar esta nueva enfermedad. Presentamos un modelo animal de neoateroesclerosis innovador junto con experimentos in vitro complementarios, en los cuales se pone de manifiesto que la integridad endotelial dañada causa una mayor permeabilidad para el colesterol de las LDL (LDL), lo que da lugar a que los monocitos se transformen en células espumosas. Asimismo, comentamos los criterios indirectos de valoración de imagen intravascular a fin de mejorar el diagnóstico fiable de la neoateroesclerosis en fase inicial. Por último, en un enfoque terapéutico para prevenir la neoateroesclerosis del stent con andamios de magnesio biorreabsorbibles (BRS) y un tratamiento sistémico con estatinas se demostró la posibilidad de mejorar la cicatrización y la reendotelización arteriales, lo que derivó en la formación de neoateroesclerosis significativamente más lenta en un modelo animal de neoateroesclerosis.

Small Dimension-Big Impact! Nanoparticle-Enhanced Non-Invasive and Intravascular Molecular Imaging of Atherosclerosis In Vivo.

Extensive translational research has provided considerable progress regarding the understanding of atherosclerosis pathophysiology over the last decades. In contrast, implementation of molecular in vivo imaging remains highly limited. In that context, nanoparticles represent a useful tool. Their variable shape and composition assure biocompatibility and stability within the environment of intended use, while the possibility of conjugating different ligands as well as contrast dyes enable targeting of moieties of interest on a molecular level and visualization throughout various imaging modalities. These characteristics have been exploited by a number of preclinical research approaches aimed at advancing understanding of vascular atherosclerotic disease, in order to improve identification of high-risk lesions prior to oftentimes fatal thromboembolic events. Furthermore, the combination of these targeted nanoparticles with therapeutic agents offers the potential of site-targeted drug delivery with minimized systemic secondary effects. This review gives an overview of different groups of targeted nanoparticles, designed for in vivo molecular imaging of atherosclerosis as well as an outlook on potential combined diagnostic and therapeutic applications.

Validation and application of OCT tissue attenuation index for the detection of neointimal foam cells.

Neointimal infiltration with foamy macrophages is recognized as an early and important sign of de-novo atherosclerosis after stent implantation (neoatherosclerosis). Recent histopathological studies have proven that automated quantification of signal attenuation using intravascular optical coherence tomography (OCT) imaging allows for sensitive identification of macrophages in native atherosclerotic disease. Whether this is true for neointimal foam cells in the setting of neoatherosclerosis remains unknown. Autopsy samples of stented coronary arteries (n = 13 cases) were evaluated by histology and OCT. After co-registration with histology, the attenuation rate of emitted laser light was measured in regions with and without neointimal foamy macrophages relative to its peak intensity at the blood-tissue interface. Attenuation index was subsequently determined as slope of a regression curve fitted to individual data points. Receiver operating curve (ROC) analysis was used to establish an optimal cut-off for detecting foamy macrophages in homogenous and non-homogenous neointima, respectively. Finally, the tissue attenuation index was applied to confirm or exclude the presence of neointimal foamy macrophages in symptomatic patients presenting with in-stent restenosis and undergoing intravascular OCT imaging (n = 29 cases). Tissue attenuation index derived from post-mortem samples differed significantly between histologically confirmed regions with and without neointimal foamy macrophages (- 1.23 ± 1.42 vs. - 0.52 ± 1.79, p < 0.05). ROC analysis was able to distinguish neointima with foamy macrophage infiltration from neointima without (93% sensitivity, 73% specificity, cut-off - 0.79, AUC 0.87 for homogenous neointima and 40% sensitivity, 95% specificity, cut-off - 1.93, AUC 0.69 for non-homogenous neointima). In symptomatic patients presenting with in-stent restenosis after stent implantation and undergoing intravascular imaging with OCT, neointimal foamy macrophages were detected in 34.2% of homogenous and 43.6% of non-homogenous neointimal ROI's evaluated. OCT-derived and histopathologically validated tissue attenuation index enables identification of neointimal foamy macrophages in stented coronary arteries. Such image-based post-processing software algorithm may help discern and triage subjects at increased risk for device-related events.

Preclinical investigation of neoatherosclerosis in magnesium-based bioresorbable scaffolds versus thick-strut drug-eluting stents.

AIMS: Neoatherosclerosis is a frequent finding after implantation of permanent metallic stents. Bioresorbable scaffolds (BRS) are considered to reduce the incidence of neoatherosclerosis owing to their dissolution and consequent vascular restoration. The aim of this study was to evaluate the formation of neoatherosclerosis between magnesium-based BRS and thick-strut metallic drug-eluting stents (DES) in a rabbit model of neoatherosclerosis and in proportion to the effect of high-dose statin medication. METHODS AND RESULTS: Fully bioresorbable magnesium scaffolds (BRS, n=45) and thick-strut permanent metallic DES of equivalent geometry and design (n=45) were implanted into the iliac arteries of New Zealand White rabbits (n=45) following endothelial balloon injury and exposure to a cholesterol diet. Endothelialisation was assessed in 12 animals after 35 days using scanning electron microscopy (SEM), showing significantly enhanced re-endothelialisation above struts in the BRS (n=13) compared to DES (n=10). Eleven (11) animals were terminated for baseline assessment after 91 days while the remaining 22 animals were randomised to receive high-dose statin treatment (3 mg/kg) or placebo. BRS-treated vessels showed a significant reduction in foam cell infiltration as a sign of early neoatherosclerosis by histology and OCT when compared to thick-strut DES-treated vessels. Statin treatment resulted in significant reduction of foam cell infiltration in BRS and DES by histology. CONCLUSIONS: Our findings suggest reduced neoatherosclerosis formation in magnesium-based BRS relative to thick-strut DES. High-dose statin treatment may be a promising measure to reduce neoatherosclerosis progression, both on its own and in synergy with site-targeted device-based treatment.

Assessment of a pro-healing stent in an animal model of early neoatherosclerosis.

BACKGROUND: Neoatherosclerosis represents an accelerated manifestation of atherosclerosis in nascent neointima after stenting, associated with adverse events. We investigated whether improved reendothelialization using RGD-coated stents results in diminished vascular permeability and reduced foam cell formation compared to standard DES in atherosclerotic rabbits. METHODS AND RESULTS: Neointimal foam cell formation was induced in rabbits (n = 7). Enhanced endothelial integrity in RGD-coated stents resulted in decreased vascular permeability relative to DES, which was further confirmed by SEM and TEM. Cell culture experiments examined the effect of everolimus on endothelial integrity. Increasing concentrations of everolimus resulted in a dose-dependent decrease of endothelial cell junctions and foam cell transformation of monocytes, confirming the relevance of endothelial integrity in preventing permeability of LDL. CONCLUSION: Incomplete endothelial integrity was confirmed as a key factor of neointimal foam cell formation following stent implantation. Pro-healing stent coatings may facilitate reendothelialization and reduce the risk of neoatherosclerosis.

Preclinical evaluation of degradation kinetics and elemental mapping of first- and second-generation bioresorbable magnesium scaffolds.

AIMS: Because vascular restoration therapy using bioresorbable vascular scaffolds (BRS) remains an appealing concept to restore vasoreactivity, an understanding of biodegradation remains paramount during preclinical testing. We therefore aimed to investigate the qualitative and temporal course of degradation of magnesium alloy-based bioresorbable vascular scaffolds in juvenile swine. METHODS AND RESULTS: Qualitative characterisation of biodegradation was performed in 41 DREAMS 1G up to three years, while degradation kinetics were acquired in 54 DREAMS 2G implanted into porcine coronary arteries for 28, 90 and 180 days, one and two years. Assessment of end product composition was achieved in DREAMS 2G at 180 days. Myocardium was examined, while an OCT attenuation score was derived at strut level from 180 days to two years in DREAMS 2G. Degradation of DREAMS entails two corrosive phases. At one year, 94.8% of the magnesium was bioabsorbed in DREAMS 2G and, at two years, magnesium was completely replaced by amorphous calcium phosphate. Von Kossa staining revealed variable peri-strut mineralisation at all time points and only small focal myocardial emboli observed in one animal in the 180 days cohort. Strut discontinuity density was low at 28 days (0.5±0.57 per mm) and increased to a density above 7.5 per mm up to one year. OCT attenuation score correlated well with strut-based degradation analysis up to two years. CONCLUSIONS: While the current set of data supports vascular safety, clinical trials are warranted to prove the concept of vascular restoration following DREAMS implantation.

Neoatherosclerosis in Patients With Coronary Stent Thrombosis: Findings From Optical Coherence Tomography Imaging (A Report of the PRESTIGE Consortium).

OBJECTIVES: The purpose of this study was to assess neoatherosclerosis in a registry of prospectively enrolled patients presenting with stent thrombosis using optical coherence tomography. BACKGROUND: In-stent neoatherosclerosis was recently identified as a novel disease manifestation of atherosclerosis after coronary stent implantation. METHODS: Angiography and intravascular optical coherence tomography were used to investigate etiologic factors of neoatherosclerosis in patients presenting with stent thrombosis >1 year after implantation (very late stent thrombosis [VLST]). Clinical data were collected according to a standardized protocol. Optical coherence tomographic acquisitions were analyzed in a core laboratory. Cox regression analysis was performed to identify factors associated with the formation of neoatherosclerosis and plaque rupture as a function of time. RESULTS: Optical coherence tomography was performed in 134 patients presenting with VLST. A total of 58 lesions in 58 patients with neoatherosclerosis were compared with 76 lesions in 76 patients without neoatherosclerosis. Baseline characteristics were similar between groups. In-stent plaque rupture was the most frequent cause (31%) in all patients presenting with VLST. In patients with neoatherosclerosis, in-stent plaque rupture was identified as the cause of VLST in 40 cases (69%), whereas uncovered stent struts (n = 22 [29%]) was the most frequent cause in patients without neoatherosclerosis. Macrophage infiltration was significantly more frequent in optical coherence tomographic frames with plaque rupture compared with those without (50.2% vs. 22.2%; p < 0.0001), whereas calcification was more often observed in frames without plaque rupture (17.2% vs. 4%; p < 0.0001). Implantation of a drug-eluting stent was significantly associated with the formation of neoatherosclerosis (p = 0.02), whereas previous myocardial infarction on index percutaneous coronary intervention was identified as a significant risk factor for plaque rupture in patients with neoatherosclerosis (p = 0.003). No significant difference was observed in thrombus composition between patients with or without neoatherosclerosis. CONCLUSIONS: Neoatherosclerosis was frequently observed in patients with VLST. Implantation of a drug-eluting stent was significantly associated with neoatherosclerosis formation. In-stent plaque rupture was the prevailing pathological mechanism and often occurred in patients with neoatherosclerosis and previous myocardial infarction at index percutaneous coronary intervention. Increased macrophage infiltration heralded plaque vulnerability in our study and might serve as an important indicator.

Cell adhesive peptides functionalized on CoCr alloy stimulate endothelialization and prevent thrombogenesis and restenosis.

Immobilization of bioactive peptide sequences on CoCr surfaces is an effective route to improve endothelialization, which is of great interest for cardiovascular stents. In this work, we explored the effect of physical and covalent immoblization of RGDS, YIGSR and their equimolar combination peptides on endothelial cells (EC) and smooth muscle cell (SMC) adhesion and on thrombogenicity. We extensively investigated using RT-qPCR, the expression by ECs cultured on functionalised CoCr surfaces of different genes. Genes relevant for adhesion (ICAM-1 and VCAM-1), vascularization (VEGFA, VEGFR-1 and VEGFR-2) and anti-thrombogenicity (tPA and eNOS) were over-expressed in the ECs grown to covalently functionalized CoCr surfaces compared to physisorbed and control surfaces. Pro-thrombogenic genes expression (PAI-1 and vWF) decreased over time. Cell co-cultures of ECs/SMCs found that functionalization increased the amount of adhered ECs onto modified surfaces compared to plain CoCr, independently of the used peptide and the strategy of immobilization. SMCs adhered less compared to ECs in all surfaces. All studied peptides showed a lower platelet cell adhesion compared to TCPS. Covalent functionalization of CoCr surfaces with an equimolar combination of RGDS and YIGSR represented prevailing strategy to enhance the early stages of ECs adhesion and proliferation, while preventing SMCs and platelet adhesion. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 973-983, 2017.

Biofunctionalization of REDV elastin-like recombinamers improves endothelialization on CoCr alloy surfaces for cardiovascular applications.

To improve cardiovascular implant success, metal-based stents are designated to modulate endothelial cells adhesion and migration in order to prevent restenosis and late thrombosis diseases. Biomimetic coatings with extra-cellular matrix adhesive biomolecules onto stents surfaces are a strategy to recover a healthy endothelium. However, the appropriate bioactive sequences to selective promote growth of endothelium and the biomolecules surface immobilization strategy remains to be elucidated. In this study, biofunctionalization of cobalt chromium, CoCr, alloy surfaces with elastin-like recombinamers, ELR, genetically modified with an REDV sequence, was performed to enhance metal surfaces endothelialization. Moreover, physical adsorption and covalent bonding were used as biomolecules binding strategies onto CoCr alloy. Surfaces were activated with plasma and etched with sodium hydroxide previous to silanization with 3-chloropropyltriethoxysilane and functionalized with the ELR. CoCr alloy surfaces were successfully biofunctionalized and the use of an ELR with an REDV sequence, allows conferring bioactivity to the biomaterials surface, demonstrating a higher cell adhesion and spreading of HUVEC cells on the different CoCr surfaces. This effect is emphasized as increases the amount of immobilized biomolecules and directly related to the immobilization technique, covalent bonding, and the increase of surface charge electronegativity. Our strategy of REDV elastin-like recombinamers immobilization onto CoCr alloy surfaces via covalent bonding through organosilanes provides a bioactive surface that promotes endothelial cell adhesion and spreading.

Recromía en un diente del maxilar superior / Tooth bleaching in the maxilla

Se describe el caso clínico de una paciente de 28 años de edad, quien acudió a la consulta de atención integral de la Clínica Estomatológica Provincial Docente Mártires del Moncada de Santiago de Cuba por presentar cambio de color en un diente anterosuperior izquierdo. Se indicó radiografía periapical que mostró tratamiento pulpo radicular en ese diente. Se decidió realizar la técnica de blanqueamiento para discromía de origen orgánico en 3 o 4 sesiones. Se obtuvo el resultado esperado y la paciente quedó satisfecha.

The case report of a 28 year-old patient who went to the comprehensive care service of Mártires del Moncada Provincial Teaching Stomatological Clinic in Santiago de Cuba for presenting a change of color in the anterosuperior left tooth is described. Periapical X-ray was indicated that showed pulpar radicular treatment in that tooth. It was decided to carry out the blenching technique for dyschromia of organic origin for 3 or 4 sessions. The expected result was obtained and the patient was satisfied.

Factores de riesgo de afecciones bucodentales en niños de guarderías infantiles no estatales / Risk factors of oral-dental disorders in children from particular daycare houses

Se realizó un estudio observacional, descriptivo, de corte transversal desde enero hasta mayo de 2017 de 93 niños de 1-4 años matriculados en 5 guarderías infantiles no estatales del reparto Sueño de Santiago de Cuba, con el objetivo de identificar los factores riesgo que incidieron en las enfermedades bucales que presentaban. Para recoger la información se confeccionó una planilla elaborada a los efectos y realizó el interrogatorio a padres y niños, además del examen bucal a estos últimos. Entre los factores de riesgo prevalecieron la dieta cariogénica (96,7 %), seguida por el uso del biberón (59,1 %); asimismo, la maloclusión resultó ser la alteración más frecuente, principalmente el resalte aumentado y la mordida abierta. Aunque predominaron los pacientes sin afectación, estaban expuestos a dichos factores. Por tanto, se debe insistir en el diagnóstico precoz de las maloclusiones para minimizar o evitar su impacto negativo sobre la salud de los menores.

An observational, descriptive and cross-sectional study, of 93 children aged 1-4 years registered in 5 non-state daycare houses in Sueño neighborhood of Santiago de Cuba was carried out from January to May, 2017, with the objective of identifying the risk factors which influenced in the oral illnesses that they presented. To collect the information a schedule was made for this aim and an inquiry to parents and children was carried out, besides the oral examination to the last ones. Among the risk factors the cariogenic diet (96.7 %), followed by the use of the baby bottle (59.1 %) prevailed; also, the malocclusion turned out to be the most frequent disorder, mainly the increased prominence and the open bite. Although the patients without disorders prevailed, they were exposed to these factors. Therefore, it should be insisted in the previous diagnosis of malocclusions to minimize or to avoid their negative impact on the health of the children.

Enfermedades bucales y factores de riesgo en la población geriátrica perteneciente a un consultorio médico / Oral diseases and risk factors in the geriatric population of a family doctor's office

Se realizó un estudio descriptivo y transversal, desde noviembre de 2016 hasta abril de 2017, de los 166 adultos mayores pertenecientes al consultorio médico No 20 del Policlínico Carlos Juan Finlay del municipio de Santiago de Cuba, para evaluar la presencia de enfermedades bucodentales y los factores de riesgo. Para la recolección de la información se utilizó la encuesta de salud bucal de la Organización Mundial de la Salud y la historia de salud bucal familiar. Los hábitos nocivos como la deficiente higiene bucal y la dieta cariogénica, además de las enfermedades crónicas no transmisibles, fueron los factores de riesgo más comunes en esta población, en quienes la disfunción masticatoria y la caries dental constituyeron los problemas principales

A descriptive and cross-sectional study of 166 elderly belonging to the family doctor office No 20 of Carlos J Finlay Polyclinic in the municipality of Santiago de Cuba, was carried out from November, 2016 to April, 2017, to evaluate the presence of oral-dental diseases and risk factors. The survey of oral health from the World Health Organization and the medical record of family oral health were used for gathering the information. Harmful habits as poor oral hygiene and a cariogenic diet, besides non communicable chronic diseases, were the most common risk factors in this population, for whom masticatory dysfuntion and dental decay constituted the main problems

Dientes supernumerarios en el maxilar superior / Supernumerary teeth in the maxilla

Se describe el caso clínico de un niño de 10 años de edad, atendido en la consulta de atención integral de la Clínica Estomatológica Provincial Docente de Santiago de Cuba, quien presentaba 2 dientes supernumerarios en el maxilar, detectados mediante la radiografía panorámica antes de comenzar el tratamiento ortodóncico. Se indicó la extracción quirúrgica y se observó el aspecto conoide que comúnmente presentan dichos dientes. El seguimiento clínico posterior reveló la ausencia de alteraciones en las estructuras anatómicas y una correcta cicatrización de los tejidos blandos.

The case report of a 10 year-old boy is described, assisted in the comprehensive care department of the Teaching Provincial Estomatological Clinic from Santiago de Cuba who presented 2 supernumerary teeth in the maxilla, detected by means of the panoramic x-ray before beginning the orthodontic treatment. The surgical extraction was indicated and the conoid aspect that commonly present these teeth was observed. The subsequent clinical follow-up revealed the absence of changes in the anatomical structures and a correct scaring of the soft tissues.

Sistemas de apoyo social y control metabólico en la diabetes mellitus / Social support systems and metabolic control in diabetes mellitus

Se estudia la relación existente entre los sistemas de apoyo social y el control metabólico en pacientes diabéticos. Se analizan 31 sujetos diagnosticados con diabetes mellitus (11 insulino dependientes y 20 no insulinodependientes) a los cuales se les aplicó la escala Hiemler de funcionamiento social y se valoró el control metabólico a través de una determinación de hemoglobina glicosilada (Hb A1). Se encontraron correlaciones significativas entre variables psicológicas de apoyo social y los valores de Hb A1, en la muestra total, por sexo y tipo de diabetes